Methamphetamine (METH) abuse impairs host defense mechanisms and is thought to enhance host susceptibility to infections. High incidence of HIV-1 infection in METH abusers and potential effects of METH on the immune system underscore the clinical significance of METH-HIV-1 co-morbidity. Although METH abuse is implicated in dysregulation of immunity, the causal interrelationship between METH exposure and the inability to elicit protective adaptive immune response remains elusive. Acquired immunity, in particular CD8+T cell response, plays a pivotal role in control of HIV-1 infection. Lack of understanding of impact of METH abuse on acquired immune response in controlling HIV-1 infection warrants future considerations. Our preliminary data showed that METH exposure increased cytosolic calcium levels in primary human T cells leading to generation of ROS that correlated with mitochondrial injury and T cell dysfunction. We found that METH exposure altered gene expression regulating cell signaling, proliferation and differentiation, cell-mediated immune responses and transcriptional co-activation potentially contributing to METH-mediated T cell dysfunction. For the first time, we showed that trace amine associated receptor (TAAR1, a novel receptor activated by amines) is stimulated by METH on T cells implying that some of METH effects may be attributable to activity of this receptor. Using a combination of in vitro (molecular, biochemical and functional assays) and in vivo animal models of chronic viral infection (SCID mouse model for HIV-1 encephalitis and LCMV mouse model) chronically exposed to METH, we will address the following questions: (1) What are the pathophysiological effects of METH on T cell mitochondrial dynamics? (2) What are the underlying mechanisms and molecular consequences of METH-mediated mitochondrial dysfunction on T cells and what roles do they play in cell immune cell impairment? (3) What effects does METH-mediated immune dysfunction have on the host adaptive immune responses to chronic viral infections (HIV-1/LCMV infection)? We will identify mitochondrial substrates of METH and delineate pathways involved in these effects by using proteomic and molecular biological approaches. The proposed work is highly significant, as it will contribute to understanding of the underlying mechanisms of the combined effects of HIV-1 and METH abuse on adaptive immunity. Therapeutic approaches towards boosting T cell immunity based on these investigations will reduce persistent infection. PUBLIC HEALTH RELEVANCE: Methamphetamine, a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. Current proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.